JPH0372416A - Dermal administration drug - Google Patents

Dermal administration drug

Info

Publication number
JPH0372416A
JPH0372416A JP2136332A JP13633290A JPH0372416A JP H0372416 A JPH0372416 A JP H0372416A JP 2136332 A JP2136332 A JP 2136332A JP 13633290 A JP13633290 A JP 13633290A JP H0372416 A JPH0372416 A JP H0372416A
Authority
JP
Japan
Prior art keywords
absorption
acid
transdermal
water
preparation
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
JP2136332A
Other languages
Japanese (ja)
Inventor
Masayuki Yamada
正幸 山田
Muneo Nonomura
宗夫 野々村
Kohei Nishikawa
浩平 西川
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nitto Denko Corp
Takeda Pharmaceutical Co Ltd
Original Assignee
Nitto Denko Corp
Takeda Chemical Industries Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nitto Denko Corp, Takeda Chemical Industries Ltd filed Critical Nitto Denko Corp
Publication of JPH0372416A publication Critical patent/JPH0372416A/en
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
    • A61K9/7061—Polyacrylates

Abstract

PURPOSE:To obtain the subject dermal administration drug capable of controlling release of an active component and absorption accelerants and having a long duration of pharmacological action by blending the active component with a water soluble absorption accelerant, a fat soluble absorption accelerant and a high water-absorptive resin. CONSTITUTION:With 0.1-20wt.% active component, 0.1-80wt.% water soluble substance (e.g. propylene glycol) and 0.1-80wt.% fat soluble substance (e.g. isopropyl myristate) respectively capable of promoting dermal absorption of the above-mentioned active component and 0.1-10wt.% high water-absorptive resin (e.g. saponified vinyl acetate-acrylate copolymer) are blended. ln addition thereto, a nonionic surfactant, an inorganic base, an acid and a known base are mixed in to prepare and obtain the objective drug. Preparation is carried out preferably in forms of patch, cataplasm, ointment, plaster, tape, etc.

Description

【発明の詳細な説明】 産業上の利用分野 本発明は、０）薬効成分、（ｉｉ）該薬効成分の経度吸
収を促進する水溶性物質、（ｉｉｉ）該薬効成分の経皮
吸収を促進する脂溶性物質、および（ｉｖ）高吸水性樹
脂を含有してなる経皮用製剤に関する。DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention provides: 0) a medicinal ingredient, (ii) a water-soluble substance that promotes transdermal absorption of the medicinal ingredient, and (iii) a water-soluble substance that promotes transdermal absorption of the medicinal ingredient. The present invention relates to a transdermal preparation containing a fat-soluble substance and (iv) a superabsorbent resin.

従来の技術 近年、薬物を経皮投与し全身作用を狙った製剤、いわゆ
るＴｒａｎｓｄｅｒｍａｌ　　Ｔｈｅｒａｐｅｕｔｉｃ
　　Ｓｙｓｔｅｍ（ＴＴＳ）に多大の関心がもたれ、す
でにいくつかの経皮製剤が開発されている。狭心症の予
防・治療剤のニトログリセリン、硝酸インソルビット、
降圧剤のクロニジンなどを含有するＴＴＳがそれである
。上記したニトログリセリンなどの薬物はそれ自身経度
吸収されやすい物性であり、また低い血中濃度で薬効を
あられすので製剤化の容易な薬物であるといえる。一方
、多くの薬物は経皮吸収されにくい物性を有するため、
吸収を促進させる必要が生じる。吸収促進の方法として
は、吸収促進剤を配合する方法、あるいはイオント７オ
レシスや超音波による方法などがあげられ、吸収促進剤
による吸収促進の研究が活発に行われているが、十分な
成果が得られているとはいい難い。これ迄いくつかの吸
収促進剤が報告されており、その中でも脂肪族カルボン
酸、その低級アルコールエステルおよび脂肪族アルコー
ルなど、薬効成分の経皮吸収を促進する脂溶性物質（以
下、脂溶性吸収促進剤と略記することがある）およびア
ルカンポリオールなど、薬効成分０経皮吸収を促進する
水溶性物質（以下、水溶性吸収促進剤と略記することが
ある）をそれぞれ一種以上含有する多成分系吸収促進剤
は、吸収促進効果が優れているうえに、皮膚刺激も小さ
くまたそれぞれ使用前例のある成分であるので好ましい
促進剤であることが本発明者らによって見い出されてい
る（特願昭６３−２２２０８１号明細書参照）。Conventional technology In recent years, so-called Transdermal Therapeutic drugs have been developed by transdermally administering drugs to achieve systemic effects.
There has been a great deal of interest in TTS (TTS), and several transdermal formulations have already been developed. Nitroglycerin, insorbitol nitrate, preventive and therapeutic agents for angina pectoris,
One example is TTS, which contains the antihypertensive drug clonidine. Drugs such as the above-mentioned nitroglycerin have physical properties that allow them to be easily absorbed over time, and they are effective at low blood concentrations, so they can be said to be drugs that can be easily formulated. On the other hand, many drugs have physical properties that make it difficult for them to be absorbed through the skin.
It becomes necessary to promote absorption. Methods for promoting absorption include adding an absorption enhancer, or using ionto-7-oresis and ultrasonic waves.Research on promoting absorption using absorption enhancers is actively being conducted, but sufficient results have not been obtained. It's hard to say that I'm getting it. Several absorption enhancers have been reported so far, including fat-soluble substances (hereinafter referred to as fat-soluble absorption enhancers) that promote transdermal absorption of medicinal ingredients, such as aliphatic carboxylic acids, their lower alcohol esters, and aliphatic alcohols. A multi-component absorption system containing one or more water-soluble substances that promote percutaneous absorption of medicinal ingredients (hereinafter sometimes abbreviated as water-soluble absorption enhancers), such as alkane polyols (sometimes abbreviated as water-soluble absorption enhancers) The present inventors have found that accelerators are preferable accelerators because they have an excellent absorption promoting effect, cause little skin irritation, and each ingredient has a precedent for its use (Japanese Patent Application No. 1983-1999). 222081).

これら多成分系吸収促進剤の配合量は、薬物の物性やそ
の有効血中濃度の大小などに応じ実験を行って決定され
る。しかしながら、経度用製剤の設計、製造において、
これら多成分系吸収促進剤の配合に起因して生ずる問題
が多々ある。例えば、上記脂溶性吸収促進剤および水溶
性吸収促進剤の相溶性に起因する問題がそれである。両
者は相溶性がきわめて悪く、特にテープ剤などの場合、
用いる粘着剤と吸収促進剤との相溶性が悪いためテープ
剤となし得ないこともあり、またテープ剤を製すること
ができても、経口に従って分離の生じることがある。さ
らにまた、貼布剤を製するとき水をはじめとする水溶性
成分や、脂溶性成分が配合されることが多く、このよう
な場合に於いても相溶性が問題となる。このような問題
の解決に対して、界面活性剤あるいは界面活性作用のあ
る高分子、例えばポリビニルピロリドンなどを配合する
方法が知られている。しかしながら、配合される吸収促
進剤の物性あるいは配合量によっては、これらの界面活
性剤あるいは高分子が有効に働かないことが多い。その
ために、設計通り薬効成分の経度吸収がなされず薬理作
用が不十分なことがあり問題となる。The amount of these multi-component absorption enhancers to be blended is determined through experiments depending on the physical properties of the drug and its effective blood concentration. However, in the design and manufacture of medicinal preparations,
There are many problems that arise due to the formulation of these multi-component absorption enhancers. For example, this is a problem caused by the compatibility of the above-mentioned fat-soluble absorption enhancer and water-soluble absorption enhancer. The two have extremely poor compatibility, especially in the case of tapes, etc.
Due to poor compatibility between the adhesive used and the absorption enhancer, it may not be possible to form a tape preparation, and even if a tape preparation can be prepared, separation may occur during oral administration. Furthermore, when preparing a patch, water-soluble components such as water and fat-soluble components are often blended, and compatibility becomes a problem in such cases as well. In order to solve these problems, a method is known in which a surfactant or a polymer having a surfactant effect, such as polyvinylpyrrolidone, is added. However, these surfactants or polymers often do not work effectively depending on the physical properties or amount of the absorption enhancer to be blended. Therefore, medicinal ingredients may not be absorbed longitudinally as designed, resulting in insufficient pharmacological action, which poses a problem.

発明が解決しようとする課題 本発明者らは、薬効成分と、水溶性および脂溶性吸収促
進剤の多成分系吸収促進剤とを含有する貼布剤（テープ
剤）などの経皮用製剤の設計、製造において、高吸水性
樹脂を配合することによって、意外にも脂溶性成分と水
溶性成分との分離あるいはこれらと粘着剤との分離が抑
制されることを見い出した。また、経口安定性も向上し
、均一な組成の経皮用製剤が得られることを確認し、さ
らに研究を進め本発明を完成した。Problems to be Solved by the Invention The present inventors have developed a transdermal preparation such as a patch (tape) containing a medicinal ingredient and a multi-component absorption enhancer including water-soluble and fat-soluble absorption enhancers. It has been surprisingly found that by incorporating a superabsorbent resin in the design and manufacturing process, separation of fat-soluble components and water-soluble components or separation of these components from the adhesive can be suppressed. Furthermore, it was confirmed that oral stability was improved and a transdermal preparation with a uniform composition could be obtained, and further research was conducted to complete the present invention.

課題を解決するための手段 本発明は前記のとおり、（ｉ）薬効成分、（ｉｉ）該薬
効成分の経皮吸収を促進する水溶性物質、（ｉｌｉ）該
薬効成分の経皮吸収を促進する脂溶性物質、および（ｉ
ｖ）高吸水性樹脂を含有してなる経皮用製剤を提供する
ものである。Means for Solving the Problems As described above, the present invention provides (i) a medicinal ingredient, (ii) a water-soluble substance that promotes transdermal absorption of the medicinal ingredient, and (ili) a water-soluble substance that promotes transdermal absorption of the medicinal ingredient. a fat-soluble substance, and (i
v) A transdermal preparation containing a super absorbent resin is provided.

本発明による経皮用製剤に用いられる薬効成分「成分（
ｉ）］は、製剤設計の目的上、経皮吸収されにくい物性
の薬物が望ましく用いられるが、経皮吸収により全身作
用が期待される薬物であればいずれでもよく特に限定さ
れない。具体的には、心臓・血管系薬剤（例、（Ｒ）−
３−［（Ｓ）−１−カルボキシ−５−（４−ピペリジル
）ペンチル］アミ７−４−オキソー２．３．４．５−テ
トラヒドロ−１，５−ベンゾチアゼピン−５−酢酸（以
下、化合物（１）と略記することがある）［特開昭６０
−２３１６６８号公報参照］、デラプリル、カプトプリ
ルなとのアンジオテンシン夏変換酵素阻害剤；ピンドロ
ール、プロプラノロールなどのアドレナリンβレセプタ
ー遮断薬；クロニジンなどのアドレナリンａ２レセプタ
ーアゴニスト；二７エジビンなどのＣａ拮抗剤；などの
降圧剤、ニトログリセリン、硝酸イソソルビット、モル
シドミンなどの冠血管拡張剤、ジゴキシンなどの強心配
糖体、シフランデレートなどの末梢血管拡張剤、ビンポ
セチンなどの脳循環代謝改善剤など）、脳神経系薬剤（
例、ジアゼバン、イミビラミンなどの向神経薬、ｄＭ−
塩酸メチルエフェドリンなどの自律神経作用系、ジフェ
ンヒドラミンなどの鎮うん剤、サリチル酸などの解熱・
鎮痛薬など）、呼吸器系薬剤（例、エピネフリンなどの
気管支拡張剤など）、消化器系薬剤（例、スコポラミン
などの消化管鎮けい剤など）、内分泌代謝系薬剤（例、
インドメタシンなどの痛風治療剤、ビタミンＤ、ビタミ
ンＥなどのビタミン剤、ＬＨ−ＲＨ，ＴＲＨなとのポリ
ペプチド系ホルモン剤、テストステロンなどのアンドロ
ゲン剤、エストラジオールなどのエストロゲン剤、コル
チコステロイドなどの副賢皮質ステロイド剤）、抗腫瘍
剤（例、５−フルオロウラシルなど）などをあげること
ができる。これらの薬剤は任意の量配合することができ
、配合量は用いられる薬効成分の種類、使用目的などに
よって異なるが、通常００１〜２０％（Ｗ／Ｗ）の配合
量が好ましく用いられる。また薬効成分は、水溶性薬物
、脂溶性薬物のいずれであってもよく、また相互作用に
よる不都合が生じない場合には複数の薬物を経皮製剤中
に含有させることも可能である。The medicinal ingredients used in the transdermal preparation according to the present invention are:
i)], for the purpose of formulation design, it is desirable to use a drug with physical properties that make it difficult to be absorbed through the skin, but it is not particularly limited and may be any drug that is expected to have systemic effects through transdermal absorption. Specifically, cardiovascular drugs (e.g., (R)-
3-[(S)-1-carboxy-5-(4-piperidyl)pentyl]ami7-4-oxo2.3.4.5-tetrahydro-1,5-benzothiazepine-5-acetic acid (hereinafter referred to as (sometimes abbreviated as compound (1))
-231668], angiotensin converting enzyme inhibitors such as delapril and captopril; adrenergic beta receptor blockers such as pindolol and propranolol; adrenergic A2 receptor agonists such as clonidine; Ca antagonists such as 27edivin; Antihypertensive drugs, coronary vasodilators such as nitroglycerin, isosorbitol nitrate, and molsidomine, cardiac glycosides such as digoxin, peripheral vasodilators such as siflanderate, cerebral circulation and metabolism improving agents such as vinpocetine, etc.), and drugs for the nervous system. (
e.g., neurotropic drugs such as diazeban, imiviramine, dM-
Autonomic nervous system agents such as methylephedrine hydrochloride, antidepressants such as diphenhydramine, and antipyretics such as salicylic acid.
analgesics), respiratory drugs (e.g., bronchodilators such as epinephrine), gastrointestinal drugs (e.g., gastrointestinal antispasmodics such as scopolamine), endocrine-metabolic drugs (e.g.,
Gout treatments such as indomethacin, vitamins such as vitamin D and vitamin E, polypeptide hormones such as LH-RH and TRH, androgens such as testosterone, estrogen drugs such as estradiol, and supplementary drugs such as corticosteroids. corticosteroids), antitumor agents (eg, 5-fluorouracil, etc.), and the like. Any amount of these drugs can be blended, and the blend amount varies depending on the type of medicinal ingredient used, the purpose of use, etc., but a blend amount of 0.001 to 20% (W/W) is usually preferably used. Furthermore, the medicinal ingredient may be either a water-soluble drug or a fat-soluble drug, and it is also possible to include multiple drugs in a transdermal preparation if no inconvenience due to interaction occurs.

高吸水性樹脂［成分（ｉｖ）］としては、自重の数十倍
から千倍以上の水を吸収することができる高分子であり
、水に膨潤してヒドロゲルを形威し、圧力を加えても水
が脱離しない樹脂があげられ、具体的には酢酸ビニル−
アクリル酸エステル共重合体ケン化物、ポリアクリル酸
塩系、ポリビニルアルコール−無水マレイン酸共重合体
架橋物、インブチレン−マレイン酸共重合体架橋物、ポ
リアクリロニトリルグラフト重合体ケン化物、デンプン
−アクリル酸グラフト重合体などをあげることができ、
なかでも自重の約５０〜２０００倍の水を吸収できる高
分子が好ましい。本発明の経皮用製剤への高吸水性樹脂
の配合量は任意であるが、好ましくは０．１−１０％（
Ｗ／Ｗ）程度、より好ましくは０．５〜５％（Ｗ／Ｗ）
程度である。Super absorbent resin [component (iv)] is a polymer that can absorb water tens to thousands of times its own weight, swells in water to form a hydrogel, and when pressure is applied. Examples include resins that do not release water, specifically vinyl acetate.
Saponified acrylic ester copolymer, polyacrylate-based, crosslinked polyvinyl alcohol-maleic anhydride copolymer, crosslinked inbutylene-maleic acid copolymer, saponified polyacrylonitrile graft polymer, starch-acrylic acid Examples include graft polymers,
Among these, polymers that can absorb about 50 to 2000 times their own weight of water are preferred. The amount of superabsorbent resin to be added to the transdermal preparation of the present invention is arbitrary, but preferably 0.1-10% (
W/W) degree, more preferably 0.5 to 5% (W/W)
That's about it.

薬効成分の経皮吸収を促進する脂溶性物質（脂溶性吸収
促進剤）［成分（ｉｉ）］としては、例えば炭素数６〜
２０の脂肪族カルボン酸、その低級アルコールエステル
および炭素数６〜２０の脂肪族アルコールなどがあげら
れる。The fat-soluble substance (fat-soluble absorption enhancer) [component (ii)] that promotes transdermal absorption of medicinal ingredients is, for example, a substance having 6 to 6 carbon atoms.
Examples include aliphatic carboxylic acids having 20 carbon atoms, lower alcohol esters thereof, and aliphatic alcohols having 6 to 20 carbon atoms.

前記炭素数６〜２０の脂肪族カルボン酸としては、たと
えばカプロン酸、カプリル酸、カプリン酸、ラウリン酸
、ミリスチン酸、バルミチン酸、ステアリン酸、アラキ
ン酸、トウハク酸、リンデル酸、オレイン酸、リノール
酸、リルン酸、アラキドン酸、セバシン酸などの飽和も
しＸは不飽和の脂肪族モノカルボン酸またはジカルボン
酸があげられる。炭素数６〜２０の脂肪族カルボン酸の
低級アルコールエステルとしては、たとえば前記の炭素
数６〜２０の脂肪族カルボン酸の炭素数ｌ〜５程度の低
級アルコール（例、メタノール、エタノール、プロパノ
ール、２−プロパノール、ブタノール、ペンタノール）
エステルなどがあげられる。脂肪族ジカルボン酸の低級
アルコールエステルには、一方もしくは両方のカルボキ
シル基がエステル化されＩ；モノおよびジエステルが含
まれる。炭素数６〜２０の脂肪族カルボン酸の低級アル
コールエステルの具体例としては、セバシン酸ジエステ
ル、ミリスチン酸イソプロピルなどがあげられる。Examples of the aliphatic carboxylic acids having 6 to 20 carbon atoms include caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, valmitic acid, stearic acid, arachidic acid, tuccinic acid, lindelic acid, oleic acid, and linoleic acid. X is an unsaturated aliphatic monocarboxylic acid or dicarboxylic acid such as phosphoric acid, arachidonic acid, and sebacic acid. Examples of lower alcohol esters of aliphatic carboxylic acids having 6 to 20 carbon atoms include lower alcohols having 1 to 5 carbon atoms of the aliphatic carboxylic acids having 6 to 20 carbon atoms (e.g., methanol, ethanol, propanol, 2 -propanol, butanol, pentanol)
Examples include esters. Lower alcohol esters of aliphatic dicarboxylic acids include mono- and diesters in which one or both carboxyl groups are esterified. Specific examples of lower alcohol esters of aliphatic carboxylic acids having 6 to 20 carbon atoms include diester sebacate and isopropyl myristate.

前記炭素数６〜２０脂肪族アルコールとしては、たとえ
ばカプロイルアルコール、カプリルアルコール、カプリ
ルアルコール、ラウリルアルコール、ミリスチルアルコ
ール、セチルアルコール、ステアリルアルコール、オレ
イルアルコール、リルイルアルコール、リルニルアルコ
ールなどの飽和もしくは不飽和の脂肪族アルコールがあ
げられる。Examples of the aliphatic alcohol having 6 to 20 carbon atoms include saturated or unsaturated alcohols such as caproyl alcohol, caprylic alcohol, caprylic alcohol, lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, oleyl alcohol, rylyl alcohol, and lylunyl alcohol. Examples include saturated aliphatic alcohols.

脂肪族カルボン酸、脂肪族カルボン酸の低級アルコール
エステルおよび脂肪族アルコールの中でも脂肪族モノカ
ルボン酸の低級（Ｃｔ−Ｓ）アルコールエステルがより
好ましく、最も好ましくはミリスチン酸イソプロピルで
ある。Among aliphatic carboxylic acids, lower alcohol esters of aliphatic carboxylic acids, and aliphatic alcohols, lower (Ct-S) alcohol esters of aliphatic monocarboxylic acids are more preferred, and isopropyl myristate is most preferred.

薬効成分の経皮吸収を促進する水溶性物質（水溶性吸収
促進剤）［成分（ｉｉ）］としては、例えばアルカンポ
リオールなどがあげられる。Examples of the water-soluble substance (water-soluble absorption enhancer) [component (ii)] that promotes transdermal absorption of medicinal ingredients include alkane polyols.

アルカンポリオールとしては、たとえばエチレンクリコ
ール（１，２−エタンジオール）、プロピレングリコー
ル（ｌ、２−プロパンジオール）、１．３−プロパンジ
オール、１．２−ブタンジオールｌ１１３−ブタンジオ
ール、ｌ、４−ブタンジオール、２゜３−ブタンジオー
ル、ｌ、５−ベンタンジオールなどの炭素数２〜５程度
の低級アルカンジオールやグリセリンなどの炭素数２〜
５の低級アルカントリオールがあげられる。なかでもプ
ロピレングリコールおよび１．３−ブタンジオールが好
ましい。Examples of the alkane polyol include ethylene glycol (1,2-ethanediol), propylene glycol (l,2-propanediol), 1,3-propanediol, 1,2-butanediol, 113-butanediol, l,4 -Lower alkanediols with about 2 to 5 carbon atoms, such as butanediol, 2゜3-butanediol, l,5-bentanediol, and 2 to 5 carbon atoms, such as glycerin.
5 lower alkanetriols are mentioned. Among them, propylene glycol and 1,3-butanediol are preferred.

上記吸収促進剤は、脂溶性吸収促進剤の一種以上および
水溶性吸収促進剤の一種以上を併用する。The above absorption enhancer is a combination of one or more fat-soluble absorption enhancers and one or more water-soluble absorption enhancers.

経皮用製剤中の脂溶性吸収促進剤および水溶性吸収促進
剤の配合量は任意であるが、好ましくは各々０．１〜８
０％程度、より好ましくは１〜５０％（Ｗ／Ｗ）程度で
ある。The amount of the fat-soluble absorption enhancer and water-soluble absorption enhancer in the transdermal preparation is arbitrary, but preferably 0.1 to 8.
It is about 0%, more preferably about 1 to 50% (W/W).

また、成分（ｆｆｌ）としての脂肪族カルボン酸または
脂肪族アルコールは製剤中に好ましくは０．５〜１０％
（Ｗ／Ｗ）程度、より好ましくは０．５〜５％（Ｗ／Ｗ
）程度となるように配合される。成分（ｉｉ）としての
脂肪族カルボン酸の低級アルコールエステルは製剤中に
好ましくは１〜５０％（Ｗ／Ｗ）程度、より好ましくは
５〜３０％（Ｗ／Ｗ）程度となるように配合される。複
数種の脂肪族カルボン酸、脂肪族カルボン酸の低級アル
コールエステルまたは脂肪族アルコールを用いる場合、
脂肪族カルボン酸の合計量は好ましくは０．５〜２０％
（Ｗ／Ｗ）程度、より好ましくは０．５〜１０％（Ｗ／
Ｗ）程度、脂肪族カルボン酸の低級アルコールエステル
の合計量は好ましくは１〜５０％（Ｗ／Ｗ）程度、より
好ましくは５〜３０％（Ｗ／Ｗ）程度、脂肪族アルコー
ルの合計量は好ましくは０゜５〜２０％（Ｗ／Ｗ）程度
、より好ましくは０．５〜ｌＯ％（Ｗ／Ｗ）程度である
。In addition, the aliphatic carboxylic acid or aliphatic alcohol as a component (ffl) is preferably 0.5 to 10% in the formulation.
(W/W) degree, more preferably 0.5 to 5% (W/W)
). The lower alcohol ester of aliphatic carboxylic acid as component (ii) is preferably blended in the formulation at a concentration of about 1 to 50% (W/W), more preferably about 5 to 30% (W/W). Ru. When using multiple types of aliphatic carboxylic acids, lower alcohol esters of aliphatic carboxylic acids, or aliphatic alcohols,
The total amount of aliphatic carboxylic acids is preferably 0.5-20%
(W/W), more preferably 0.5 to 10% (W/W)
W), the total amount of lower alcohol ester of aliphatic carboxylic acid is preferably about 1 to 50% (W/W), more preferably about 5 to 30% (W/W), and the total amount of aliphatic alcohol is Preferably it is about 0.5 to 20% (W/W), more preferably about 0.5 to 10% (W/W).

製剤中の成分（ｎ）としてのアルカンポリオールの配合
量は好ましくは１〜５０％（Ｗ／Ｗ）程度、より好まし
くは１〜３０％（Ｗ／Ｗ）程度である。The amount of the alkane polyol as component (n) in the formulation is preferably about 1 to 50% (W/W), more preferably about 1 to 30% (W/W).

本発明の経皮用製剤中には各成分をより均一に混合する
ため、非イオン性界面活性剤が添加されることが好まし
い。A nonionic surfactant is preferably added to the transdermal preparation of the present invention in order to mix each component more uniformly.

非イオン性界面活性剤としては、ポリオキシエチレンソ
ルビタン脂肪酸エステル（例、ポリオキシエチレンソル
ビタンモノオレエート、ポリオキシエチレンソルビタン
モノステアレート、ポリオキシエチレンンルビタンモノ
パルミテート、ホリオキシエチレンンルビタンモノラウ
レートなど）、ポリオキシエチレンンルビトール脂肪酸
エステル（例、ポリオキシエチレンソルビトールモノラ
ウレートなど）、ポリオキシエチレン脂肪酸エステル（
例、ポリオキシエチレンステアレートなど）、ポリオキ
シエチレン高級アルコールエーテル（例、ポリオキシエ
チレンラウリルアルコール、ポリオキシエチレンオレイ
ルアルコールなど）、ポリオキシエチレンアルキルアリ
ールエーテル（例、ポリオキシエチレンノニルフェノー
ルなど）、ポリオキシエチレンヒマシ油誘導体（例、Ｈ
ＣＯ−３０、ＨＣＯ−６０などのポリオキシエチレン硬
化ヒマシ油誘導体など）、ポリオキシエチレンラノリン
誘導体、ポリオキシエチレンラノリンアルコール誘導体
、ブロックポリマー型非イオン性界面活性剤（例、プル
ロニック、Ｌ−６２，Ｌ−６４゜Ｆ〜６８など）があげ
られる。これら非イオン性界面活性剤の配合量はＨＬＢ
が５〜２０となる比率であれば全量としては任意の量配
合することが出来るが好ましくは０．５〜２０％程度、
より好ましくは０．５〜１０％程度、さらに好ましくは
１〜５％（Ｗ／Ｗ）程度である。Examples of nonionic surfactants include polyoxyethylene sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monopalmitate, holoxyethylene sorbitan monooleate, polyoxyethylene rubitol fatty acid esters (e.g. polyoxyethylene sorbitol monolaurate), polyoxyethylene fatty acid esters (e.g. polyoxyethylene sorbitol monolaurate),
(e.g., polyoxyethylene stearate, etc.), polyoxyethylene higher alcohol ether (e.g., polyoxyethylene lauryl alcohol, polyoxyethylene oleyl alcohol, etc.), polyoxyethylene alkylaryl ether (e.g., polyoxyethylene nonylphenol, etc.), Oxyethylene castor oil derivatives (e.g. H
polyoxyethylene hydrogenated castor oil derivatives such as CO-30 and HCO-60), polyoxyethylene lanolin derivatives, polyoxyethylene lanolin alcohol derivatives, block polymer type nonionic surfactants (e.g. Pluronic, L-62, L-64°F~68, etc.). The amount of these nonionic surfactants is HLB
Any amount can be blended as long as the ratio is 5 to 20, but preferably about 0.5 to 20%.
More preferably, it is about 0.5 to 10%, and even more preferably about 1 to 5% (W/W).

本発明の製剤中には、さらに無機塩基を添加してもよく
、無機塩基としては、たとえばアルカリ金属の水酸化物
（例、水酸化す）　ＩＪウム、水酸化カリウム）、アル
カリ金属炭酸塩（例、炭酸ナトリウム、炭酸カリウム）
、アルカリ金属炭酸水素塩（例、炭酸水素ナトリウム、
炭酸水素カリウム）などがあげられる。添加される無機
塩基の量は用いられる無機塩基の種類にもよるが、一般
に０．０２〜５％（Ｗ／Ｗ）程度であり、製剤のｐＨが
６〜９程度となるよう添加される。無機塩基としてアル
カリ金属水酸化物またはアルカリ金属炭酸水素塩を用い
る場合、薬効成分１モルに対して通常０．８〜１．２モ
ル程度、アルカリ金属炭酸塩を用いる場合、薬効成分１
モルに対して通常０．４〜０．６モル程度の無機塩基が
好ましく用いられる。また、上記した無機塩基のほかに
、塩酸あるいはクエン酸などの酸を添加して用いること
もできる。これらは、薬効成分の溶解に用いられるので
配合量は任意である。In the preparation of the present invention, an inorganic base may be further added, and examples of the inorganic base include alkali metal hydroxides (e.g., potassium hydroxide, potassium hydroxide), alkali metal carbonates ( e.g., sodium carbonate, potassium carbonate)
, alkali metal bicarbonate (e.g., sodium bicarbonate,
Examples include potassium hydrogen carbonate). The amount of inorganic base added depends on the type of inorganic base used, but is generally about 0.02 to 5% (W/W), and is added so that the pH of the preparation is about 6 to 9. When using an alkali metal hydroxide or alkali metal hydrogen carbonate as an inorganic base, it is usually about 0.8 to 1.2 mol per mol of the medicinal ingredient, and when using an alkali metal carbonate, it is usually about 1 mol of the medicinal ingredient.
Usually about 0.4 to 0.6 mole of inorganic base is preferably used. Furthermore, in addition to the above-mentioned inorganic bases, acids such as hydrochloric acid or citric acid can also be added. Since these are used to dissolve medicinal ingredients, the amount to be added is arbitrary.

本発明の経皮用製剤にはバッチ剤、バッグ剤、軟膏剤（
クリーム剤も含む）、硬膏剤、テープ剤、坐剤。The transdermal preparations of the present invention include batch preparations, bag preparations, ointments (
(including creams), plasters, tapes, and suppositories.

ローション剤、液剤、懸濁剤、乳剤、噴霧剤などが含ま
れるが、なかでも経皮用貼布剤（バッチ剤、パップ剤、
硬膏剤、テープ剤など）が好ましい。軟膏剤（クリーム
剤を含む）、坐剤、ローション剤、液剤、懸濁剤、乳剤
、噴霧剤は、上記成分（ｉ　）、（ｉｉ　）、（ｉｉｉ
）および（ｉｖ）、および必要に応じ非イオン性界面活
性剤、無機塩基、酸を製剤分野において自体公知の溶剤
、懸濁化剤、乳化剤、噴射剤、軟膏基剤、坐剤基剤など
とともに配合して製することができる。必要により、防
腐剤（例、パラオキシ安息香酸エチル。It includes lotions, solutions, suspensions, emulsions, sprays, etc., but especially transdermal patches (batches, poultices,
plasters, tapes, etc.) are preferred. Ointments (including creams), suppositories, lotions, solutions, suspensions, emulsions, and sprays contain the above ingredients (i), (ii), and (iii).
) and (iv), and if necessary, nonionic surfactants, inorganic bases, acids, together with solvents, suspending agents, emulsifiers, propellants, ointment bases, suppository bases, etc. that are known per se in the formulation field. It can be manufactured by blending. If necessary, preservatives (e.g., ethyl paraoxybenzoate).

塩化ベンザルコニウムなど）、炎症防止剤（例、グリチ
ルリチン酸など）などを配合することもできる。パッチ
剤、バッグ剤、硬膏剤、テープ剤などの貼布剤は、上記
成分（ｉ）、（ｉｉ）、（ｉｉｉ）および（ｉｖ）、お
よび必要に応じ非イオン性界面活性剤、無機塩基、酸な
らびに製剤分野において自体公知の基剤を混合し、必要
に応じて防腐剤、炎症防止剤などを加えた後、適当な担
持体に吸収または付着させ調製することができる。担持
体としては高分子膜。Benzalkonium chloride, etc.), anti-inflammatory agents (eg, glycyrrhizic acid, etc.), etc. can also be added. Patches such as patches, bags, plasters, and tapes contain the above components (i), (ii), (iii), and (iv), and if necessary, a nonionic surfactant, an inorganic base, It can be prepared by mixing an acid and a base known per se in the pharmaceutical field, adding preservatives, anti-inflammatory agents, etc. as necessary, and then absorbing or adhering to a suitable carrier. A polymer membrane is used as a support.

織布、不織布１紙などがあげられる。パッチ剤、バッグ
剤、テープ剤に必要に応じて使用される粘着剤としては
ポリアルキルビニルエーテル系、ポリアルキルアクリレ
ート系［特公昭５８−２３８４６号公報参照］、ポリイ
ソグチレン系、天然ゴム系。Examples include woven fabric, non-woven fabric, and paper. Adhesives used as needed in patches, bags, and tapes include polyalkyl vinyl ether, polyalkyl acrylate (see Japanese Patent Publication No. 58-23846), polyisobutylene, and natural rubber.

合皮ゴム系粘着剤があげられる。また適度の可塑性と粘
着性を保持させるために動物油（例、スクワレン、スク
ワランなど）、植物油（例、オリーブ油、ホホバ油など
）、ワセリン、ラノリンなどが加えられてもよい。Examples include synthetic leather and rubber adhesives. Further, animal oil (eg, squalene, squalane, etc.), vegetable oil (eg, olive oil, jojoba oil, etc.), vaseline, lanolin, etc. may be added to maintain appropriate plasticity and tackiness.

軟膏剤、硬膏剤、坐剤、テープ剤、バッチ剤、パップ剤
などを調製する際には、経皮吸収を調節する成分、たと
えばレシチンなどのリン脂質、固形パラフィン、ミツロ
ウ、カルナウバロウ、硬化ヒマシ油、ラノリン、ワセリ
ン、ポリビニルアルコール、ポリビニルピロリドン、ポ
リエチレングリコール、グリセリン脂肪酸エステル、コ
レステロール、カーボポール、カルボキシメチルセルロ
ース、カルボキシエチルセルロース、シリコン樹脂、低
級アルコール（例、エタノール、イソプロピルアルコー
ル等）などを配合することができる。When preparing ointments, plasters, suppositories, tapes, batches, poultices, etc., ingredients that regulate transdermal absorption, such as phospholipids such as lecithin, solid paraffin, beeswax, carnauba wax, and hydrogenated castor oil, are used. , lanolin, vaseline, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol, glycerin fatty acid ester, cholesterol, carbopol, carboxymethyl cellulose, carboxyethyl cellulose, silicone resin, lower alcohol (e.g. ethanol, isopropyl alcohol, etc.), etc. can be blended. .

溶剤としては水、エタノール、グリセリンなどがあげら
れる。懸濁化剤、乳化剤としては、アラビアゴム、カル
ボキシメチルセルロース、メチルセルロース、アルギン
酸ナトリウムなどがあげられる。Examples of the solvent include water, ethanol, and glycerin. Examples of suspending agents and emulsifying agents include gum arabic, carboxymethyl cellulose, methyl cellulose, and sodium alginate.

噴射剤としては、不燃性液化ガス（例、フレオン１１．
７レオン１２．７レオン１１３など）などがあげられる
。軟膏基剤としては、ワセリン、固形パラフィン、植物
油、動物油、鉱物油、ラノリン、ろう類、マクロゴール
類などがあげられる。硬膏基剤としてはミツろう、パラ
フィン、マクロゴール類。As a propellant, a nonflammable liquefied gas (eg, Freon 11.
7 Leon 12.7 Leon 113, etc.). Examples of ointment bases include petrolatum, solid paraffin, vegetable oil, animal oil, mineral oil, lanolin, waxes, and macrogol. Plaster bases include beeswax, paraffin, and macrogol.

グリセリン脂肪酸エステル類などがあげられる。Examples include glycerin fatty acid esters.

坐剤基剤としてはカカオ脂、ラノリン脂、マクロゴール
、ウィテップゾール、グリセロゼラチンなどがあげられ
る。Suppository bases include cocoa butter, lanolin fat, macrogol, witepsol, glycerogelatin, and the like.

本発明の経皮用製剤の身体の皮膚への適用は、投与対象
の症状などによって異なるが、成人の高血圧症の治療の
目的で化合物ＣＩ）を投与する場合、薬効成分［化合物
（１）〕として通常１回量１〜２００ｍｇ程度、好まし
くはｌＯ〜１５０ａ＋ｇ程度を１〜７日毎に１回、好ま
しくは１日１回投与（貼布、塗布、噴霧、直腸挿入）す
ることにより行われる。The application of the transdermal preparation of the present invention to the skin of the body varies depending on the symptoms of the subject, but when administering compound CI) for the purpose of treating hypertension in adults, the medicinal ingredient [compound (1)] It is usually administered by administering a dose of about 1 to 200 mg, preferably about 10 to 150 a+g, once every 1 to 7 days, preferably once a day (by patch, application, spray, or rectal insertion).

また、貼布剤の場合、身体のどの部位に貼布してもよい
。In the case of a patch, it may be applied to any part of the body.

各成分の混合および経皮用製剤の調製は、自体公知の方
法、たとえば日本薬局方などに記載の方法により行うこ
とができる。Mixing of each component and preparation of a transdermal preparation can be performed by methods known per se, for example, methods described in the Japanese Pharmacopoeia.

成分（ｉ）が無機塩基もしくは酸の存在下または非存在
下で水に溶解する物質あるいは成分（ｉｉ）に溶解する
物質である場合、成分（ｉ）、　（ｉｉ）および（ｉｖ
Ｘならびに必要により無機塩基または酸）を水の存在下
にあらかじめ混合し、成分（ｉ）および（■）を水とと
もに成分（ｉｔ　）に吸収させた後、成分（燻）または
成分（ｉｉｉ）および非イオン性界面活性剤の混合物に
分散させることが好ましい。成分（ｉｉ）または成分（
瓜）および非イオン性界面活性剤の混合物は適当な有機
溶媒（例、酢酸エチル）に溶解して用いてもよい。分散
後、必要により得られた混合物は乾燥工程に付される。If component (i) is a substance that is soluble in water or soluble in component (ii) in the presence or absence of an inorganic base or acid, components (i), (ii) and (iv)
X and optionally an inorganic base or acid) in the presence of water, and after absorption of components (i) and (■) together with water into component (it ), component (smoking) or component (iii) and Preferably, it is dispersed in a mixture of nonionic surfactants. Component (ii) or component (
A mixture of a melon) and a nonionic surfactant may be used by dissolving it in a suitable organic solvent (eg, ethyl acetate). After dispersion, the resulting mixture is subjected to a drying step, if necessary.

成分（ｉ）が脂溶性物質である場合、成分（ｎ）を水と
ともに成分（ｉｖ）に吸収させた後、成分（ｉ）および
（斑）の混合物またはこれらと非イオン性界面活性剤と
の混合物に分散させることが好ましい。When component (i) is a fat-soluble substance, component (n) is absorbed into component (iv) together with water, and then a mixture of component (i) and (spot) or a combination of these with a nonionic surfactant is prepared. Preferably, it is dispersed in a mixture.

成分（ｉ）および（ｉｎ）の混合物またはこれらと非イ
オン性界面活性剤の混合物は適当な有機溶媒（例、酢酸
エチル）に溶解して用いてもよい。分散後、必要により
得られた混合物は乾燥工程に付される。A mixture of components (i) and (in) or a mixture of these and a nonionic surfactant may be used after being dissolved in a suitable organic solvent (eg, ethyl acetate). After dispersion, the resulting mixture is subjected to a drying step, if necessary.

作用および効果 本発明による経皮用製剤は高吸水性樹脂の配合により、
配合成分の分離がないので、薬効成分および吸収促進剤
の放出が制御され、設計通りの薬効成分の経皮吸収が見
られ、その薬理作用も十分かつ長時間に亘って持続する
。したがって本発明の経皮用製剤は、種々の疾病の予防
治療製剤として哺乳動物（例えばヒト、サル、イヌ、ネ
コなど）の身体皮膚に適用することができる。Actions and Effects The transdermal preparation according to the present invention has a super absorbent resin.
Since there is no separation of the ingredients, the release of the medicinal ingredients and absorption enhancer is controlled, the medicinal ingredients are absorbed transdermally as designed, and the pharmacological action is sustained for a sufficient length of time. Therefore, the transdermal preparation of the present invention can be applied to the body skin of mammals (eg, humans, monkeys, dogs, cats, etc.) as preventive and therapeutic preparations for various diseases.

実施例 以下に実施例を示して本発明をさらに詳しく説明するが
、本発明はこれらに限定されるべきものではない。EXAMPLES The present invention will be explained in more detail with reference to Examples below, but the present invention should not be limited thereto.

実施例１ ［経皮用貼布剤の調製１ アンジオテンシン変換酵素阻害剤である（Ｒ）−３−［
（Ｓ）−１−カルボキシ−５−（４−ピペリジル）ペン
チル］アミノー４−オキソー２，３，４．５＝テトラヒ
ドロ−１，５−ベンゾチアゼピン−５−酢酸［化合物（
Ｉ）］ｌＯｇ、水５０ｔｇ、プロピレングリコール２Ｑ
ｇ、　ＮａＯＨ１，１５ｇ−および高吸水性樹脂［酢酸
ビニル−アクリル酸エステル共重合体ケン化物（住友化
学製：スミカゲル５Ｐ−５１０）］］ｇを混合溶解して
水相とした。次に、ｌｔ［エチルにポリアルキルアクリ
レート系粘着剤［日本カーバイド工業製：ニカゾール　
ＴＳ−６２０（アクリル酸メチル・アクリル酸−２−エ
チルヘキシル共重合樹脂エマルジ３ン）のポリマー分精
製品１４３ｇ、　Ｔｗｅｅｎ　８０　５　ｇ、およびイ
ソプロビルミリステー１２０ｇを混合溶解して油相とし
た。先に得られた水相を油相と十分に混合し、ポリエチ
レンシート上に乾燥後の膏体の厚みが約１００μｍとな
るように塗膏したのち、８０℃で５分間乾燥した。乾燥
後セパレーター（離けい用シート）でおおい経皮用貼布
剤（テープ剤）とした。Example 1 [Preparation of transdermal patch 1 Angiotensin converting enzyme inhibitor (R)-3-[
(S)-1-carboxy-5-(4-piperidyl)pentyl]amino-4-oxo2,3,4.5=tetrahydro-1,5-benzothiazepine-5-acetic acid [compound (
I)] 10g, water 50tg, propylene glycol 2Q
g, 15 g of NaOH and g of a super absorbent resin [saponified vinyl acetate-acrylic acid ester copolymer (manufactured by Sumitomo Chemical: Sumikagel 5P-510)] were mixed and dissolved to form an aqueous phase. Next, lt
143 g of a polymer fractionated product of TS-620 (methyl acrylate/2-ethylhexyl acrylate copolymer resin emulsion), 5 g of Tween 80, and 120 g of isoprobyl myrite were mixed and dissolved to form an oil phase. The aqueous phase obtained above was thoroughly mixed with the oil phase, and the mixture was applied onto a polyethylene sheet so that the thickness of the dried paste was approximately 100 μm, and then dried at 80° C. for 5 minutes. After drying, it was covered with a separator (separation sheet) to form a transdermal patch (tape).

［経皮吸収実験］ 雄性ＳＤラット９週令の除毛した腹部皮膚（６ｃＩ１１
つにテープ剤（化合物（Ｉ）として６ＩＩ１ｇ／ラット
）を２４時間貼布し密封包帯した。経皮吸収性の評価は
経口的にアンジオテンシンＩ昇圧反応抑制率（％）を測
定しておこなった。なお、アンジオテンシンＩは３００
　ｎｇ／　ｋｇ（ラット）静脈投与した。また、吸収の
程度および持続はアンジオテンシン■昇圧反応抑制８０
％以上が投与何時間後に認められるか、またその持続時
間は何時間であるかを指標とした。[Percutaneous absorption experiment] Dehaired abdominal skin of 9-week-old male SD rats (6cI11
A tape preparation (1 g of 6II/rat as compound (I)) was applied to the mouse for 24 hours and a sealed bandage was applied. Percutaneous absorption was evaluated by orally measuring the angiotensin I pressor response inhibition rate (%). Furthermore, angiotensin I is 300
ng/kg (rat) was administered intravenously. In addition, the degree and duration of absorption are determined by angiotensin ■ pressor response inhibition 80
% or more was observed after administration and for how many hours was the duration.

［結　果］ 吸収促進剤と粘着剤とが分離することなく、表面が平滑
で一様の厚さのテープ剤が得られた。また、４０℃３力
月、室温６力月経過後も分離は認められなかった。化合
物（Ｉ）は十分に経皮吸収され、アンジオテンシンＩ昇
圧反応抑制８０％は投与後５時間で認められ、これが２
４時間以上持続した。[Results] A tape preparation with a smooth surface and a uniform thickness was obtained without separation of the absorption promoter and adhesive. Further, no separation was observed after 3 months at 40°C and 6 months at room temperature. Compound (I) was sufficiently absorbed transdermally, and 80% inhibition of angiotensin I pressor response was observed 5 hours after administration, and this
Lasted over 4 hours.

実施例２ ［経皮用貼布剤の調製］ 化合物（１０５ｇ、水７０ｄ、プロピレングリコール１
５ｇ、ｌ、３−ブチレングリコール１０ｇ。Example 2 [Preparation of transdermal patch] Compound (105 g, water 70 d, propylene glycol 1
5g, l,3-butylene glycol 10g.

ＮａＯＨ１−１５ｇ−および高吸水性樹脂〔酢酸ビニル
−アクリル酸エステル共重合体ケン化物（住友化学製：
スミカゲル５Ｐ−５１０）］　］ｇを混合溶解し水相と
した。次に、酢酸エチルにポリアルキルビニルエーテル
系粘着剤〔ポリビニルエチルエーテル（Ｔｇニー３０６
Ｃ）／ポリビニルエチルエーテル（Ｔｇ　ニー６０’Ｃ
）＝６０部／４０部コ３３ｇ５Ｔｖｅｅｎ８０　５　ｇ
、およびインプロビルミリステー１１５ｇを混合溶解し
て油相とし、先に得られた水相と十分に混合した。ポリ
エチレンシート上に乾燥後の膏体の厚みが約１００μｍ
となるように塗膏し、ｌＯＯ′Ｃで３分間乾燥した。乾
燥後セパレーターでおおい経皮用貼布剤（テープ剤）と
した。1-15 g of NaOH and super absorbent resin [Saponified vinyl acetate-acrylic acid ester copolymer (manufactured by Sumitomo Chemical:
Sumikagel 5P-510)]g was mixed and dissolved to form an aqueous phase. Next, a polyalkyl vinyl ether adhesive [polyvinylethyl ether (Tgney 306)] was added to ethyl acetate.
C)/Polyvinylethyl ether (Tg knee 60'C
)=60 parts/40 parts 33g5Tveen80 5g
, and 115 g of Improvil Myriste were mixed and dissolved to form an oil phase, which was thoroughly mixed with the previously obtained aqueous phase. The thickness of the plaster after drying on the polyethylene sheet is approximately 100 μm.
It was applied as a plaster and dried at lOO'C for 3 minutes. After drying, it was covered with a separator to form a transdermal patch (tape).

［経皮吸収実験］ 実施例１に記載の方法によりおこなっｔ；。[Transdermal absorption experiment] It was carried out by the method described in Example 1.

［結　果］ 吸収促進剤と粘着剤とが分離することなく、表面が平滑
で一様の厚さのテープ剤が得られた。[Results] A tape preparation with a smooth surface and a uniform thickness was obtained without separation of the absorption promoter and adhesive.

４０℃３力月、室温６力月経過後も分離は認められなか
った。また、化合物（Ｉ）は十分経皮吸収され、アンジ
オテンシン■昇圧反応抑制８０％は投与後３時間で認め
られ、これが２４時間以上持続した。No separation was observed even after 3 months at 40°C and 6 months at room temperature. Further, Compound (I) was sufficiently absorbed through the skin, and 80% inhibition of angiotensin pressor response was observed 3 hours after administration, and this continued for more than 24 hours.

実施例３ ［経皮用貼布剤の調製〕 化合物（Ｉ）１０ｇ、水５０−、プロピレングリコール
２０ｇ、ＮａＯＨ１，１５ｇ、および高吸水性樹脂［ポ
リアクリル酸塩系（住友化学製：スミカゲルＮＰ−１０
１０）］　　Ｉｇを混合溶解し水相とした。次に、酢酸
エチルにポリアルキルアクリレート系粘着剤［日本カー
バイド工業製：ニカゾール　ＴＳ−６２０（アクリル酸
メチル・アクリル酸−２−エチルヘキシル共重合樹脂エ
マルジョン）のポリマー分精製品］　５０ｇ、　Ｔｖｅ
ｅｎ２０　８ｇおよびオレイルアルコール１０ｇを混合
溶解して油相とした。先に得られた水相を油相と十分に
混合し、ポリエチレンシート上に乾燥後、膏体の厚みが
約１１００ｐとなるように塗青し、８０′Ｃで５分間乾
燥した。乾燥後セパレーターでおおい経皮用貼布剤（テ
ープ剤）とした。Example 3 [Preparation of transdermal patch] 10 g of compound (I), 50 g of water, 20 g of propylene glycol, 1.15 g of NaOH, and a super absorbent resin [polyacrylate-based (manufactured by Sumitomo Chemical: Sumikagel NP- 10
10)] Ig was mixed and dissolved to form an aqueous phase. Next, 50 g of a polyalkyl acrylate adhesive [manufactured by Nippon Carbide Kogyo Co., Ltd.: Nikazol TS-620 (methyl acrylate/2-ethylhexyl acrylate copolymer resin emulsion] polymer separation product] was added to ethyl acetate.
8 g of en20 and 10 g of oleyl alcohol were mixed and dissolved to form an oil phase. The previously obtained aqueous phase was thoroughly mixed with the oil phase, dried on a polyethylene sheet, painted blue so that the thickness of the paste was about 1100p, and dried at 80'C for 5 minutes. After drying, it was covered with a separator to form a transdermal patch (tape).

［経皮吸収実験Ｊ 実施例１に記載の方法によりおこなった。[Transdermal absorption experiment J The method described in Example 1 was used.

［結　果］ 吸収促進剤と粘着剤とが分離することなく、表面が平滑
で一様の厚さのテープ剤が得られた。[Results] A tape preparation with a smooth surface and a uniform thickness was obtained without separation of the absorption promoter and adhesive.

４０°Ｃ３力月、室温６力月経過後も分離は認められな
かった。また、化合物ＣＩ）は十分に吸収され、アンジ
オテンシンＩ昇圧反応抑制８０％は投与後５時間で認め
られ、これが２４時間以上持続した。No separation was observed even after 3 months at 40°C and 6 months at room temperature. Compound CI) was sufficiently absorbed, and 80% inhibition of angiotensin I pressor response was observed 5 hours after administration, and this continued for more than 24 hours.

実施例４ ［経皮用貼布剤の調製］ 化合物（Ｉ）１５ｇ、水３０ｔＱ、プロピレングリコー
ル２Ｑｇ、ＮａＯＨ１−３ｇ１および高吸水性樹脂［酢
酸ビニル−アクリル酸エステル共重合体ケン化物（住友
化学製：スミカゲル５Ｐ−５１０）Ｊｉｇを混合溶解し
て、水相とした。次に、酢酸エチルにポリアルキルアク
リレート系粘着剤［アクリル酸−２−エチルヘキシルエ
ステル５５重量部、アクリル酸メトキシエチルエステル
３０重量部および酢酸ビニル１５を置部を酢酸エチルを
溶媒として重合することによって得られた共重合体］　
　３７−７ｇ％Ｔｒｅｅｎ８０　５ｇ、およびイソプロ
ピルミリステート２０ｇを混合溶解して油相とした。先
に得られた水相を油相と十分に混合し、ポリエチレンシ
ート上に乾燥後の膏体の厚みが約１００ｐ＋ｎとなるよ
うに重責したのち、７０℃で５分間乾燥した。乾燥後セ
パレーター（離けい用シート）でおおい経皮用貼布剤（
テープ剤）とした。Example 4 [Preparation of transdermal patch] Compound (I) 15 g, water 30 tQ, propylene glycol 2 Qg, NaOH 1-3 g1 and super absorbent resin [vinyl acetate-acrylic acid ester copolymer saponified product (Sumitomo Chemical Co., Ltd.) : Sumikagel 5P-510) Jig was mixed and dissolved to form an aqueous phase. Next, a polyalkyl acrylate adhesive [55 parts by weight of acrylic acid-2-ethylhexyl ester, 30 parts by weight of acrylic acid methoxyethyl ester, and 15 parts by weight of vinyl acetate] was added to ethyl acetate and polymerized using ethyl acetate as a solvent. copolymer]
5 g of 37-7 g% Tree 80 and 20 g of isopropyl myristate were mixed and dissolved to form an oil phase. The aqueous phase obtained earlier was thoroughly mixed with the oil phase, and the paste was placed on a polyethylene sheet so that the thickness of the dried paste was about 100 p+n, and then dried at 70° C. for 5 minutes. After drying, cover the transdermal patch with a separator (separation sheet).
tape agent).

［経皮吸収実験］ 雄性ＳＤラット９週令の除毛した腹部皮膚（６ｃｍりに
テープ剤（化合物（Ｉ）として９　ｍｇ／ラット）を２
４時間貼布し密封包帯した。経皮吸収性の評価は実施例
１に従って行った。[Transdermal Absorption Experiment] Two strips of tape (9 mg/rat as Compound (I)) were applied to 6 cm of dehaired abdominal skin of 9-week-old male SD rats.
The patch was applied for 4 hours and an occlusive bandage was applied. Evaluation of transdermal absorbability was performed according to Example 1.

［結　果］ 吸収促進剤と粘着剤とが分離することなく、表面が平滑
で一様の厚さのテープ剤が得られた。また、４０”０３
力月、室温６力月経過後も分離は認められなかった。化
合物（１）は十分に経皮吸収され、アンジオテンシン■
昇圧反応抑制８０％は投与後５時間で認められ、これが
２４時間以上持続した。[Results] A tape preparation with a smooth surface and a uniform thickness was obtained without separation of the absorption promoter and adhesive. Also, 40”03
No separation was observed even after 6 months at room temperature. Compound (1) is fully absorbed through the skin, and angiotensin ■
80% inhibition of pressor response was observed 5 hours after administration, and this persisted for more than 24 hours.

実施例５ ［経皮用製剤の調製］ モルシドミン（Ｎ−エトキシカルボニル−３−モルホリ
ノシドノンイミン）５ｇをプロピレングリコール１６ｇ
および水５ｇの混液に溶解したのち、さらにスミカゲル
ＳＰ−５１０１ｇを加えてホモジナイザーで均一に混合
した。Example 5 [Preparation of transdermal preparation] 5 g of molsidomine (N-ethoxycarbonyl-3-morpholinosydnonimine) was mixed with 16 g of propylene glycol.
After dissolving in a mixed solution of 5 g of water and 5 g of water, 1 g of Sumikagel SP-5 was further added and mixed uniformly with a homogenizer.

この後Ｔｗｅｅｎ８０　３ｇおよびオレイン酸５ｇを加
えてホモジナイザーで乳化した。この乳化物０．３５ｇ
をレーヨン製不織布に含浸させ、ＷＩＮ　３　ｃｔｒｒ
”、深さｌｌ１ｌＩ＋のシリコン製容器に装着し経皮用
製剤とした。Thereafter, 3 g of Tween 80 and 5 g of oleic acid were added and emulsified using a homogenizer. 0.35g of this emulsion
impregnated into rayon non-woven fabric, WIN 3 ctrr
'', and was attached to a silicone container with a depth of 1111+ to form a transdermal preparation.

〔経皮吸収実験〕[Transdermal absorption experiment]

雄性ＳＤクラット７週令１体重２４０〜２７０ｇ、５匹
）の除毛した腹部に上記の経皮用製剤を貼布してサージ
カルチーブで固定した。ｌ、２゜４．６および２４時間
後に尾静脈から採血し、血漿中のモルシドミン濃度をＨ
ＰＬＣで測定した。The above transdermal preparation was applied to the dehaired abdomens of 5 male SD rats, 7 weeks old, 240 to 270 g, and fixed with a surgical tube. Blood was collected from the tail vein after 4.6 and 24 hours, and the plasma molsidomine concentration was determined by H
Measured by PLC.

［結　果］ 表１に示すとおり、モルシドミンは十分に経皮吸収され
、高い血中濃度を示した。[Results] As shown in Table 1, molsidomine was sufficiently absorbed through the skin and showed a high blood concentration.

表１ 一方、モルシドミン０．５ｇをプロピレングリコール３
ｇに溶解し、上記と同様に溶解液０．３５ｇを不織布に
含浸させＳＤクラット投与し血漿中モルシドミン濃度を
測定したが、検出限界以下であった。Table 1 On the other hand, 0.5 g of molsidomine was added to propylene glycol 3
A nonwoven fabric was impregnated with 0.35 g of the solution in the same manner as above and administered to SD Krat to measure the plasma molsidomine concentration, which was below the detection limit.

実施例６ ［経皮用製剤の調製］ プロピレングリコール２０ｇ１積製水５ｇの混液にＴＲ
Ｈ（Ｌ−ピログルタミル−Ｌ−ヒスチジル−Ｌ−プロリ
ンアミド）９ｇを溶解したのち、スミカゲル５Ｐ−５１
０１ｇを加えてホモジナイザーで均一に混合し、さらに
Ｔｗｅｅｎ８０５ｇを加えて均一に混合した。次にイン
プロピルミリステート２０ｇを加えて、ホモジナイザー
で乳化した。乳化物０．３５ｇをレーヨン製不織布に含
浸させ、面積３　ｃｍ”、深さＩＩ！ｌｒａのシリコン
製容器に装着し経皮用製剤とした。Example 6 [Preparation of transdermal preparation] Add TR to a mixture of 20 g of propylene glycol and 5 g of purified water.
After dissolving 9 g of H (L-pyroglutamyl-L-histidyl-L-prolinamide), Sumikagel 5P-51
01g was added and mixed uniformly with a homogenizer, and further 805g of Tween was added and mixed uniformly. Next, 20 g of inpropyl myristate was added and emulsified using a homogenizer. A nonwoven fabric made of rayon was impregnated with 0.35 g of the emulsion and placed in a silicone container with an area of 3 cm'' and a depth of II!lra to prepare a transdermal preparation.

［経皮吸収実験ｊ 雄性ＳＤクラット７週令１体重２４０〜２７０ｇ、４匹
）の除毛した腹部に上記の経皮用製剤を貼布してサージ
カルテープで固定した。０．５゜１．２．４．６および
２４時間後に尾静脈から採血し、ヘパリン処理後血液０
．５ｗｊ２に試薬（８−ヒドロキシキノリン硫酸塩０．
０１　ｇ／　ｌ　、　ＥＤＴＡ−２Ｎａ　　Ｏ，１５ｇ
／ｌおよびＴｗｅｅｎ２０　０゜０５　ｇ／　ｌを含む
水溶液）５０μαを加えて血漿を分離した。血漿中のＴ
ＲＨ濃度は以下に記載のラジオイムノアッセイによ＃７
測定した。[Transdermal absorption experiment j The above-mentioned transdermal preparation was applied to the dehaired abdomens of 4 male SD rats, 7 weeks old, 240 to 270 g, and fixed with surgical tape. 0.5゜1.2.4.6 and 24 hours later, blood was collected from the tail vein and treated with heparin.
．． 5wj2 and reagent (8-hydroxyquinoline sulfate 0.
01 g/l, EDTA-2NaO, 15g
Plasma was separated by adding 50 μα (aqueous solution containing 0.05 g/l of Tween20 and 0.05 g/l of Tween20). T in plasma
RH concentration was determined by radioimmunoassay described below #7
It was measured.

分離した血漿１００ｐ１２に０．７％牛血清アルブミン
１００μα、ＴＲＨ抗体（５００倍希釈）１００１２お
よび目′Ｉ標識ＴＲＩ（１００ｔｔＱ　（約１００００
ｄｐｏ＋）を加えて４℃で３日間インキュベイシコンし
た。次に第２抗体（抗γ−グロブリン血清１００μＱお
よび正常家兎血清ｌＯＯμＱ）を加えて４°Ｃで１日間
インキュベイジョンし、３０００ｒｐｍ遠心後上清を除
去し、沈澱物の放射活性をγカウンターで測定した。100 μα of 0.7% bovine serum albumin, 100 μα of 0.7% bovine serum albumin, 10012 TRH antibody (500-fold dilution) and 100 μα of 0.7% bovine serum albumin, and 100 μα of 0.7% bovine serum albumin were added to 100 p12 of separated plasma.
dpo+) was added and incubated at 4°C for 3 days. Next, a second antibody (100 μQ of anti-γ-globulin serum and 100 μQ of normal rabbit serum) was added and incubated at 4°C for 1 day. After centrifugation at 3000 rpm, the supernatant was removed and the radioactivity of the precipitate was measured using a γ counter. It was measured.

［結　果］ 血漿中ＴＲＨ濃度は表２に示すとおり、貼布快速やかに
上昇し、４時間後に最高血中濃度約４００　ｎｇ／−を
示し、２４時間後の血中濃度も８２゜４　ｎｇ／−と高
い濃度値を示した。[Results] As shown in Table 2, the plasma TRH concentration rose rapidly after application, reaching a maximum blood concentration of approximately 400 ng/- 4 hours later, and the blood concentration 24 hours later was 82.4 ng/-. It showed a high concentration value of /-.

表２ 一ルゲル（ｐＨ４，０，０１Ｍクエン酸−０，０２Ｍリ
ン酸ニナトリウム緩衝液系）を直径３　、２　ｃｍ、厚
さ０　、１　ｃｒｎに成型（貼布面積８　ｃｍ’、ＴＲ
ｆ（含ｆｉ１６　ｍｇ）　Ｌ、上記と同様にＳＤクラッ
ト４匹）に貼布した。血漿中ＴＲＨ濃度は上記と同様に
ラジオイムノアッセイで測定した。表３に示すとおり、
血漿中ＴＲＨ濃度は非常に低かった。Table 2 One gel (pH 4, 0,01M citric acid-0,02M disodium phosphate buffer system) was molded into a diameter of 3.2 cm and a thickness of 0.1 crn (applied area 8 cm', TR
f (containing fi16 mg) was applied to L, 4 SD rats in the same manner as above. Plasma TRH concentration was measured by radioimmunoassay in the same manner as above. As shown in Table 3,
Plasma TRH concentration was very low.

表３ 一方、２％ＴＲＨ含有１０％ポリビニルアルコ実施例７ ［経皮用製剤の調製］ ＩＮ塩酸溶液５ｇ中にビンポセチン（アポビンカミン酸
エチルエステル）２．１５ｇを溶解したのち、スミカゲ
ルＳＰ−５１０１ｇを加えホモジナイザーで均一に混合
した。この後、プロピレングリコール２０ｇを加えさら
にＴｗｅｅｎ８０５ｇを加えた後、均一になるまで混合
した。次に、インプロビルミリステー１２０ｇを加えホ
モジナイザーを用いて乳化した。　乳化物０．３５　ｇ
をレーヨン製不織布に含浸させ、面積３０Ｉ１１２、深
さ１ｍｍのシリコン製容器に装着し経皮用製剤とした。Table 3 On the other hand, Example 7 of 10% polyvinyl alcohol containing 2% TRH [Preparation of transdermal preparation] After dissolving 2.15 g of vinpocetine (apovincamic acid ethyl ester) in 5 g of IN hydrochloric acid solution, 1 g of Sumikagel SP-510 was added. Mixed uniformly with a homogenizer. Thereafter, 20 g of propylene glycol was added, and 805 g of Tween was added, followed by mixing until uniform. Next, 120 g of Improvir Myriste was added and emulsified using a homogenizer. Emulsion 0.35 g
A nonwoven fabric made of rayon was impregnated with the mixture, and the mixture was placed in a silicone container with an area of 30×112 mm and a depth of 1 mm to prepare a transdermal preparation.

［経皮吸収実験］ 雄性ＳＤクラット７退会２体重２４０〜２７０ｇ、４匹
）の除毛した腹部に上記の経皮用製剤を貼布してサージ
カルテ−／で固定した。貼布直前ならびに０．５，１．
２．４．６および２４時間後に尾静脈から採血し、ヘパ
リン処理後血漿分離した。血漿中ビンポセチン濃度は、
血漿をセップパックｃ　ｌ　８　（Ｗａｔｅｒｓ）でク
リーンアップした後ＨＰＬＣにより測定した。[Transdermal absorption experiment] The above-mentioned transdermal preparation was applied to the dehaired abdomens of 4 male SD rats (7 withdrawn rats, weight 240 to 270 g) and fixed with a surgical chart. Immediately before application and 0.5, 1.
2.4.6 and 24 hours later, blood was collected from the tail vein, treated with heparin, and then separated into plasma. Plasma vinpocetine concentration is
Plasma was measured by HPLC after cleaning up with Seppaq cl 8 (Waters).

［結　果］ 血漿中のビンポセチン濃度は、表４に示すとおり投与快
速やかに上昇し、２４時間にわたって一定濃度を維持し
た。[Results] As shown in Table 4, the vinpocetine concentration in plasma rose rapidly after administration and remained constant for 24 hours.

表４ 一方、上記と同様にビンポセチン４％水分散液０．３５
　ｇを不織布に含浸させＳＤクラット投与し血漿中ビン
ポセチン濃度を測定したが、検出限界以下であった。Table 4 On the other hand, as above, vinpocetine 4% aqueous dispersion 0.35
The concentration of vinpocetine in plasma was measured by impregnating a non-woven fabric with SD rats and measuring the concentration of vinpocetine in the plasma, which was below the detection limit.

Claims (1)

【特許請求の範囲】[Claims] （ｉ）薬効成分、（ｉｉ）該薬効成分の経皮吸収を促進
する水溶性物質、（ｉｉｉ）該薬効成分の経皮吸収を促
進する脂溶性物質、および（ｉｖ）高吸水性樹脂を含有
してなる経皮用製剤。Contains (i) a medicinal ingredient, (ii) a water-soluble substance that promotes transdermal absorption of the medicinal ingredient, (iii) a fat-soluble substance that promotes transdermal absorption of the medicinal ingredient, and (iv) a super absorbent resin. A transdermal formulation made of
JP2136332A 1989-05-25 1990-05-24 Dermal administration drug Pending JPH0372416A (en)

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JP13336489 1989-05-25
JP1-133364 1989-05-25

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AT (1) ATE107517T1 (en)
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CA2017442A1 (en) 1990-11-25
EP0399432A3 (en) 1991-05-22
DE69010076D1 (en) 1994-07-28
EP0399432B1 (en) 1994-06-22
ATE107517T1 (en) 1994-07-15
US5362497A (en) 1994-11-08
DE69010076T2 (en) 1994-12-08

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